LEUKOTRIENES AND THE BLOOD-BRAIN BARRIER

人类脑肿瘤中LTC4的含量与其含量之间存在相关性

There is a correlation between LTC4 in human brain tumors and the amount of edema surrounding tumors. Human brain tumors express arachidonate 5- lipoxygenase mRNA and the inhibition of 5-lipoxygenase will decrease blood-brain barrier (BBB) permeability in tumors. Leukotriene (LT) C4 will selectively open the blood-tumor barrier (BTB) in tumors two-fold without increasing permeability in the normal brain. On the basis of these findings we have suggested that leukotrienes could allow for increased delivery of anti-tumor drugs to tumor tissue. Conversely, inhibition of 5-lipoxygenase could reduce brain tumor edema. To investigate further leukotrienes and the concept of an enzymatic BBB: 1A) in rats with brain tumors, changes in cerebral blood flow and blood volume after intracarotid (IC) leukotriene infusions will be quantitated; and 1B) electron microscopy will be used to determine whether the mechanism by which LT's increase BBB permeability, is by opening tight junctions or increasing pinocytic transport. 2A) To identify another possible enzyme in the "enzymatic barrier," antiserum to dipeptidase (the enzyme that converts LTD4 to LTE4) is used to determine whether dipeptidase is present in rat and human brain capillaries, and if so, whether it is lost in brain tumors or ischemia. 2B) The dose response to gamma glutamyl transpeptidase (gGTP) inhibition by acivicin to LTC4 opening will be determined. To further understand the "enzymatic barrier," 3A) other vasoactive compounds, bradykinin and histamine, that may also allow selective BBB opening will be infused IC alone and in combination with leukotrienes, with and without histamine H1 and H2 receptor blockers and 5-lipoxygenase inhibitors. 3B) The effect of these compounds on cerebral blood volume will be determined. 3C) Electron microscopy will also be utilized to determine the mechanism of increased permeability. 3D) Opening of the BBB to different size molecules by these compounds will be determined. 4) 5-lipoxygenase transcripts will be further characterized in human brain tumors. 5) Studies will determine whether permeability to drugs is increased in experimental tumors after intracarotid infusion of leukotrienes and other vasoactive compounds.